Circulating tumor DNA analysis and association with relapse in patients with primary refractory multiple myeloma receiving secondary salvage therapy.
Authors: Sridurga Mithraprabhu, John Reynolds, Rose Turner, Anna Kalff, Krystal Bergin, Hang Quach, Tiffany Khong, Brian G. Durie, Andrew Spencer
Journal: Journal of Clinical Oncology (2022)

8037 Background: Multiple myeloma (MM) is an incurable plasma cell malignancy with a 5 year-median overall survival (OS) in newly diagnosed (ND) patients. Real-world data reveals that 23% of transplant eligible (TE) ND MM patients relapse within 12 months of starting first-line bortezomib (1LB) based therapy and of these ̃50% will fail secondary therapy and die within 18 months. It is currently impossible to identify these high-risk patients and genomic studies could potentially inform alternative secondary therapeutic options. We propose that circulating tumour DNA (ctDNA) analysis could provide a more holistic approach to determine genomics of high-risk patients than bone marrow (BM) tumour DNA analysis in this genetically heterogenous multi-site malignancy. Methods: Peripheral blood plasma and BM samples (n = 186) were obtained at baseline, cycle 3 day 1 (C3D1), end of the study (EOS) and/or relapse, whichever appeared earlier, from a Phase II multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 TE ND MM patients who were refractory or registered suboptimal response to 1LB (Australasian Leukaemia and Lymphoma Group - MM17 trial). Somatic variants were identified in BM or ctDNA with ultra-sensitive targeted amplicon sequencing of 22-genes known to be mutated in MM. Mutational spectrum was correlated to standard MM risk factors including International Staging System (ISS), response to 1LB and KTd, cytogenetics/FISH, lactate dehydrogenase (LDH) levels, progression-free survival (PFS) and OS. Results: Our initial analysis of ctDNA mutational proportions between patients who did not or did experience relapse on KTd revealed a significantly higher proportion of RAS/RAF (3% vs 25%), or ATM/ATR/TP53 (17% vs 41%; p &lt; 0.0001), respectively, in relapse patients. Subsequently, we correlated ctDNA RAS/RAF and/or ATM/ATR/TP53 mutational presence to standard MM risk factors. We identified a shorter PFS and OS for ISS Stage 2 and 3 compared to Stage 1 patients (p = 0.002 and p = 0.02, respectively) and a significantly higher proportion of RAS/RAF or ATM/ATR/TP53 mutations in patients with refractory as compared to sub-optimal response to 1LB therapy (p = 0.0002). Patients with RAS/RAF or ATM/ATR/TP53 mutations in ctDNA at the time of starting salvage therapy also had a shorter PFS and OS on KTd (p = 0.003 and p = 0.02, respectively). Sequential ctDNA analysis discovered that in 87.5% of patients, one or more of the dominant mutations present at the time of relapse were already present at the start of salvage therapy. Conclusions: Our analysis reveals that RAS/RAF and ATM/ATR/TP53 mutations in ctDNA could be prognostic biomarkers of response to secondary salvage therapy in primary refractory patients thus providing the opportunity to design targeted salvage treatment paradigms in high-risk MM patients.